Efficacy of platinum-based chemotherapy in metastatic breast cancer and HRD biomarkers: utility of exome sequencing

Loïck Galland,Hugo Mananet,Elise Ballot,Caroline Truntzer,Silvia Ilie,Romain Boidot,François Ghiringhelli,Courèche Kaderbhai,Anthony Bergeron,Laurent Arnould,Didier Mayeur,Sylvain Ladoire,Valentin Derangère,Isabelle Desmoulins,Juliette Albuisson,Julie Lecuelle,Audrey Hennequin

doi:10.1038/s41523-022-00395-0

Abstract

Metastatic breast cancer (MBC) is frequently managed by platinum-based chemotherapy during the disease course. The real benefit of these treatments is uncertain at advanced stages of the disease and in non-triple-negative subtypes. Since homologous recombination deficiency (HRD) could inform about tumor sensitivity to DNA-damaging agents, we aimed to determine biomarkers of genomic instability, and their link with platinum efficacy. In this single-center study, we report BRCA1/2 mutational status, HRD score and signature 3 levels, all obtained by tumor exome sequencing, in 86 patients with various subtypes of MBC and who received platinum-based chemotherapy. Overall response rate, disease control rate, PFS and PFS2/PFS1 ratio were evaluated to assess platinum-based chemotherapy efficacy. Among the 86 tumor samples analyzed, 7 harbored BRCA1/2 mutations. We found a subset of BRCA-proficient MBC with high HRD score or high S3 levels, comparable to BRCA-mutated tumors. However, these patients with high HRD score or high S3 tumor level do not seem to benefit more from platinum-based chemotherapy than the others, in terms of response rates and/or PFS, regardless of BC molecular subtype. By multivariate analysis, only the absence of liver metastases was independently associated with significantly better PFS on platinum-based chemotherapy. However, some of our exploratory analyses reveal that certain methods, when optimized, seem to associate with platinum benefit. Tumor exome sequencing methodology for quantifying HRD has to be approached systematically, and further validated and standardized prior to its clinical use. Further studies are warranted to confirm these results to guide platinum use in MBC.

Highlights

Breast cancer is the most common malignancy among women worldwide[1]
Similar results were observed concerning S3 levels, with subgroups of patients who had BRCA WT and S3-high tumor status in each BC subgroup (Fig. 1d). These results indicate that a small subset of BRCA proficient metastatic breast cancer (MBC) has genomic features associated with homologous recombination (HR), at comparable levels to those observed in their BRCA mutated counterparts
To the best of our knowledge, we report here the largest series reporting the efficacy of platinum-based chemotherapy in patients with various MBC subtypes, according to different genomic tests quantifying homologous recombination deficiency (HRD), and all based on WES

Summary

Introduction

In metastatic breast cancer (MBC), therapy goals are prolongation of survival and maintaining the quality of life. Chemotherapy is one of the most widely used systemic therapies, and many families of molecules have shown their effectiveness in MBC, even in very advanced lines of treatment. Besides mitotic spindle poisons (taxanes, eribulin), anthracyclines, or oral fluoropyrimidines, platinum salts (cisplatin or carboplatin in monotherapy or associated with gemcitabine) have shown high response rates in several studies in patients with MBC, especially in triple-negative (TNBC) subtypes, in which homologous recombination deficiency (HRD) is more frequent[2]. The addition of platinum to standard neoadjuvant chemotherapy results in greater pathological complete response (pCR) rates in patients with localized TNBC5,6. PCR rates appear to be very high, ranging from 20 to 60%, in BRCA-mutated TNBC patients treated with cisplatin monotherapy[8,9]

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